DISSOCIATION-CONSTANTS OF SEROTONIN AGONISTS IN THE CANINE BASILAR ARTERY CORRELATE TO KI VALUES AT THE 5-HT1A BINDING-SITE
- 1 January 1986
- journal article
- research article
- Vol. 236 (1), 118-125
Abstract
Attempts to correlate 5-hydroxytryptamine (5-HT) binding sites and the receptor mediating 5-HT-induced contractions in the canine basilar artery (CBA) have led to discrepant claims, particularly regarding the potencies of antagonists (which appear to act noncompetitively) in the CBA. In the classical theoretical model for noncompetitive antagonism, the antagonist does not inhibit agonist binding. Thus attempts to correlate noncompetitive antagonist pD2'' values with binding measurements are inconsistent with this model and are of questionable significance. Only agonist dissociation constants (KA values) were measured in the CBA (by the irreversible antagonist method) and correlated to binding data. Logs of these KA values did not correlate with log Ki values for the inhibiton of binding of the 5-HT2 ligand [3H] ketanserin (r = 0.2253, P > .05) or log IC50 values for inhibition of [3H]5-HT binding (r = 0.5732, P > 0.05), which labels both 5-HT1A and 5-HT1B sites. A correlation was observed between the CBA values and log Ki values for the 5-HT1A binding site subtype (r = 0.9456, P < .01). The agonist ED50 and KA values were in most cases essentially identical, which suggests that in this tissue there are no spare receptors for 5-HT. Also, identical values were obtained when apparent noncompetitive antagonists were used in a manner analogous to the irreversible antagonist method to determine KA. These findings suggest the hypothesis that the apparent noncompetitive antagonism may be produced by slow dissociation of the antagonist-receptor complex, producing a pseudoirreversible action which is unmasked due to the lack of spare receptors.This publication has 13 references indexed in Scilit:
- [H-3]-LABELED KETANSERIN (R 41 468), A SELECTIVE H-3-LABELED LIGAND FOR SEROTONIN-2 RECEPTOR-BINDING SITES - BINDING-PROPERTIES, BRAIN DISTRIBUTION, AND FUNCTIONAL-ROLE1982
- Two Distinct Central Serotonin Receptors with Different Physiological FunctionsScience, 1981
- Receptor binding profile of R 41 468, A novel antagonist at 5-HT2 receptorsLife Sciences, 1981
- Discrimination of Multiple [3H]5‐Hydroxytryptamine Binding Sites by the Neuroleptic Spiperone in Rat BrainJournal of Neurochemistry, 1981
- Neurogenic dilator and constrictor responses of pial arteries in vitro. Differences between dogs and sheep.Circulation Research, 1979
- CHARACTERISTICS OF CENTRAL 5-HT RECEPTORS AND THEIR ADAPTIVE-CHANGES FOLLOWING INTRA-CEREBRAL 5,7-DIHYDROXYTRYPTAMINE ADMINISTRATION IN THE RAT1978
- Use of the biological stimulus in determining parameters of drug action, and its relationship to the drug effect A contribution to the theory of drug actionJournal of Theoretical Biology, 1977
- The margin of safety of neuromuscular transmissionThe Journal of Physiology, 1967
- CUMULATIVE DOSE-RESPONSE CURVES .1. INTRODUCTION TO TECHNIQUE1963
- SOME QUANTITATIVE USES OF DRUG ANTAGONISTSBritish Journal of Pharmacology and Chemotherapy, 1959